Alaska Native people (AN), an underserved minority US population, have the highest reported incidence (91:100,000) and death (~35:100,000) rate from colon cancer in the world. There is overwhelming experimental and human evidence that diet drives cancer risk, irrespective of genetic background. The World Cancer Research Foundation found convincing evidence that meat increases cancer risk, and that fiber suppresses it [2, 3]. Consequently, the high risk in AN may be attributed to their remarkably low fiber (8g/d) and high meat consumption. We hypothesize that their extreme risk results from the combined effects of fiber deficiency, resulting in decreased colonic microbiota production of anti-cancer butyrate, plus the high exposure to carcinogens derived from meat, fat, smoked foods and tobacco. To explore this hypothesis, we will conduct a randomized double-blinded 4-week clinical trial in up to 100 randomizable healthy, middle-aged AN undergoing screening colonoscopy, with the objective of obtaining 60 completed interventions. The interventions will consist of either a high-dose `indigestible' resistant starch fiber supplement (42g/d) given as a drink, which will increase their daily intake to >50g/d, or a control `digestible' starch drink. To gauge potential efficacy against cancer development we will use proliferative biomarkers which can be measured sequentially in colonic mucosa obtained by sigmoidoscopy biopsy (primary endpoint). At the same time, we will investigate the mechanisms responsible for these anticipated changes by measuring the colonic microbiota composition and activity by next generation sequencing of microbial 16S-rRNA genes, and its metabolome by NMR, UPLC-M, and GC-M spectrometry, interpreted with advanced mathematical modeling. We are confident that we will achieve our endpoint because we are using a much higher dose of fiber than has been used in previous clinical trials at >50g/d, which is the level shown to be associated with minimal risk in rural Africans. Secondly, we expect that the continued high fish oil consumption by AN will enhance their responsiveness to fiber supplementation. The conduct of this molecular proof-of-concept study is essential before the conduct of a large-scale definitive clinical trial of high dose fiber supplementation in the prevention of colonic polyps and cancer. While the long-term goal will be to increase the consumption of fiber-rich foods, low cost resistant starch supplementation may offer an immediate strategy to save lives in Alaska Native people, and also in high risk African Americans and the growing populations across the globe consuming low fiber Western diets. !